US8338620B2 - Methods for the production of C-8 lactam lactone compounds - Google Patents
Methods for the production of C-8 lactam lactone compounds Download PDFInfo
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- US8338620B2 US8338620B2 US12/594,414 US59441408A US8338620B2 US 8338620 B2 US8338620 B2 US 8338620B2 US 59441408 A US59441408 A US 59441408A US 8338620 B2 US8338620 B2 US 8338620B2
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- United States
- Prior art keywords
- formula
- compound
- alkyl
- salt
- benzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related, expires
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- 238000000034 method Methods 0.000 title claims abstract description 113
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 43
- -1 lactam lactone compounds Chemical class 0.000 title claims description 116
- 150000001875 compounds Chemical class 0.000 claims abstract description 241
- 150000003839 salts Chemical class 0.000 claims abstract description 90
- 230000008569 process Effects 0.000 claims abstract description 62
- 238000006243 chemical reaction Methods 0.000 claims description 88
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 67
- 125000006239 protecting group Chemical group 0.000 claims description 58
- 229910052739 hydrogen Inorganic materials 0.000 claims description 51
- 239000001257 hydrogen Substances 0.000 claims description 50
- 239000003054 catalyst Substances 0.000 claims description 45
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 43
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 40
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 35
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
- 150000001299 aldehydes Chemical group 0.000 claims description 26
- 230000009467 reduction Effects 0.000 claims description 26
- 238000006362 organocatalysis Methods 0.000 claims description 25
- 238000005984 hydrogenation reaction Methods 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 18
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 18
- 230000003213 activating effect Effects 0.000 claims description 17
- RPMXALUWKZHYOV-UHFFFAOYSA-N nitroethene Chemical group [O-][N+](=O)C=C RPMXALUWKZHYOV-UHFFFAOYSA-N 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 238000007254 oxidation reaction Methods 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- 150000001412 amines Chemical group 0.000 claims description 13
- 230000003647 oxidation Effects 0.000 claims description 13
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 11
- 150000003951 lactams Chemical class 0.000 claims description 11
- 150000002825 nitriles Chemical group 0.000 claims description 11
- 238000011065 in-situ storage Methods 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 239000002243 precursor Substances 0.000 claims description 10
- 150000002828 nitro derivatives Chemical class 0.000 claims description 9
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
- 238000006445 Nitro-Michael reaction Methods 0.000 claims description 8
- 238000007259 addition reaction Methods 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 150000003138 primary alcohols Chemical class 0.000 claims description 6
- 125000003368 amide group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 238000006957 Michael reaction Methods 0.000 claims description 3
- 238000005580 one pot reaction Methods 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 238000005112 continuous flow technique Methods 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 43
- 230000015572 biosynthetic process Effects 0.000 abstract description 42
- 239000000543 intermediate Substances 0.000 abstract description 42
- 239000002461 renin inhibitor Substances 0.000 abstract description 25
- 229940086526 renin-inhibitors Drugs 0.000 abstract description 25
- UXOWGYHJODZGMF-QORCZRPOSA-N Aliskiren Chemical compound COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC UXOWGYHJODZGMF-QORCZRPOSA-N 0.000 abstract description 24
- 229960004601 aliskiren Drugs 0.000 abstract description 24
- 0 [1*][C@@H]1CC(C2C[C@@H]([1*])C(=O)N2C)OC1=O Chemical compound [1*][C@@H]1CC(C2C[C@@H]([1*])C(=O)N2C)OC1=O 0.000 description 78
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- 239000000243 solution Substances 0.000 description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 52
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 48
- 239000000203 mixture Substances 0.000 description 43
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 31
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 28
- 238000003756 stirring Methods 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 25
- 239000002904 solvent Substances 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 24
- 239000003921 oil Substances 0.000 description 24
- 235000019198 oils Nutrition 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 239000000047 product Substances 0.000 description 23
- 235000019439 ethyl acetate Nutrition 0.000 description 19
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 239000007858 starting material Substances 0.000 description 18
- YGHRJJRRZDOVPD-UHFFFAOYSA-N 3-methylbutanal Chemical compound CC(C)CC=O YGHRJJRRZDOVPD-UHFFFAOYSA-N 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 230000005540 biological transmission Effects 0.000 description 13
- 239000012071 phase Substances 0.000 description 13
- 239000012279 sodium borohydride Substances 0.000 description 13
- 229910000033 sodium borohydride Inorganic materials 0.000 description 13
- 238000000305 Fourier transform infrared microscopy Methods 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 125000005843 halogen group Chemical group 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 11
- LGUHWEZQUSOAKW-UHFFFAOYSA-N 2-nitroethyl benzoate Chemical compound [O-][N+](=O)CCOC(=O)C1=CC=CC=C1 LGUHWEZQUSOAKW-UHFFFAOYSA-N 0.000 description 10
- 238000006842 Henry reaction Methods 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 235000015165 citric acid Nutrition 0.000 description 9
- 230000008570 general process Effects 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 150000003254 radicals Chemical class 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 9
- 238000006845 Michael addition reaction Methods 0.000 description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 229910052736 halogen Inorganic materials 0.000 description 8
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 8
- 238000010626 work up procedure Methods 0.000 description 8
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 229910000564 Raney nickel Inorganic materials 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 7
- 238000007792 addition Methods 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 150000002081 enamines Chemical group 0.000 description 7
- 150000002596 lactones Chemical class 0.000 description 7
- 239000007800 oxidant agent Substances 0.000 description 7
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 238000012552 review Methods 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 229960001866 silicon dioxide Drugs 0.000 description 7
- 229960001945 sparteine Drugs 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- MRBANVQZLNBODL-CQSZACIVSA-N (3s)-4-methyl-3-(phenylmethoxymethyl)pentanal Chemical compound O=CC[C@@H](C(C)C)COCC1=CC=CC=C1 MRBANVQZLNBODL-CQSZACIVSA-N 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 6
- 230000001590 oxidative effect Effects 0.000 description 6
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 6
- SLRCCWJSBJZJBV-AJNGGQMLSA-N sparteine Chemical compound C1N2CCCC[C@H]2[C@@H]2CN3CCCC[C@H]3[C@H]1C2 SLRCCWJSBJZJBV-AJNGGQMLSA-N 0.000 description 6
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 238000013459 approach Methods 0.000 description 5
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 125000001624 naphthyl group Chemical group 0.000 description 5
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000004611 spectroscopical analysis Methods 0.000 description 5
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 5
- CUKWUWBLQQDQAC-VEQWQPCFSA-N (3s)-3-amino-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-carboxyethyl]carbamoyl]pyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-ox Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 CUKWUWBLQQDQAC-VEQWQPCFSA-N 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- CTYQPAODDQRXBA-UHFFFAOYSA-N 5-(5-oxooxolan-2-yl)pyrrolidin-2-one Chemical class N1C(=O)CCC1C1OC(=O)CC1 CTYQPAODDQRXBA-UHFFFAOYSA-N 0.000 description 4
- 102000005862 Angiotensin II Human genes 0.000 description 4
- 101800000733 Angiotensin-2 Proteins 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 4
- 239000007868 Raney catalyst Substances 0.000 description 4
- 102100028255 Renin Human genes 0.000 description 4
- 108090000783 Renin Proteins 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 229950006323 angiotensin ii Drugs 0.000 description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 description 4
- 150000001540 azides Chemical group 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 229960004132 diethyl ether Drugs 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 229940011051 isopropyl acetate Drugs 0.000 description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- 238000006987 Nef reaction Methods 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 239000012455 biphasic mixture Substances 0.000 description 3
- 239000007844 bleaching agent Substances 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
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- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- HLIBNTOXKQCYMV-UHFFFAOYSA-N propylsulfamic acid Chemical compound CCCNS(O)(=O)=O HLIBNTOXKQCYMV-UHFFFAOYSA-N 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910003450 rhodium oxide Inorganic materials 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229910001925 ruthenium oxide Inorganic materials 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid group Chemical class S(N)(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- VUWGVTHPASPOLV-OLXYTISPSA-N tert-butyl n-[(4s,5s,6s,8s)-3,6-dihydroxy-8-(hydroxymethyl)-2,4,9-trimethyldecan-5-yl]carbamate Chemical compound CC(C)[C@@H](CO)C[C@H](O)[C@H]([C@H](C)C(O)C(C)C)NC(=O)OC(C)(C)C VUWGVTHPASPOLV-OLXYTISPSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002948 undecyl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 239000011995 wilkinson's catalyst Substances 0.000 description 1
- UTODFRQBVUVYOB-UHFFFAOYSA-P wilkinson's catalyst Chemical compound [Cl-].C1=CC=CC=C1P(C=1C=CC=CC=1)(C=1C=CC=CC=1)[Rh+](P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 UTODFRQBVUVYOB-UHFFFAOYSA-P 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Classifications
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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
- C07C205/14—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to acyclic carbon atoms
- C07C205/15—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to acyclic carbon atoms of a saturated carbon skeleton
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- C07C205/28—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to acyclic carbon atoms of the carbon skeleton
- C07C205/29—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated
- C07C205/30—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring
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- C07C205/28—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to acyclic carbon atoms of the carbon skeleton
- C07C205/31—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C07C205/40—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups and esterified hydroxy groups bound to acyclic carbon atoms of the carbon skeleton
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- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
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- C07C205/50—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
- C07C205/51—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated
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- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/50—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
- C07C205/53—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
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- C07C45/44—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reduction and hydrolysis of nitriles
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- C07C47/00—Compounds having —CHO groups
- C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
- C07C47/277—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Definitions
- the present invention relates to novel methods to prepare C-8 lactam lactone compounds. Moreover, the present invention relates to novel intermediates obtained and employed in these methods.
- C-8 lactam lactone compounds are more specifically 5-(5-oxo-tetrahydro-furan-2-yl)pyrrolidin-2-one compounds according to formula (I) as shown below.
- Such compounds are key intermediates in the preparation of renin inhibitors, in particular 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives, or pharmaceutically acceptable salts thereof. Therefore, the present invention is also directed to useful intermediates in the preparation of these renin inhibitors as well as methods for preparing these renin inhibitors and its intermediates.
- Renin passes from the kidneys into the blood where it affects the cleavage of angiotensinogen, releasing the decapeptide angiotensin I which is then cleaved in the lungs, the kidneys and other organs to form the octapeptide angiotensin II.
- the octapeptide increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating from the adrenal glands the sodium-ion-retaining hormone aldosterone, accompanied by an increase in extracellular fluid volume which increase can be attributed to the action of angiotensin II.
- Inhibitors of the enzymatic activity of renin lead to a reduction in the formation of angiotensin I, and consequently a smaller amount of angiotensin II is produced.
- the reduced concentration of that active peptide hormone is a direct cause of the hypotensive effect of renin inhibitors.
- Such 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives are any of those having renin inhibitory activity and, therefore, pharmaceutical utility and include, e.g., those disclosed in U.S. Pat. No. 5,559,111. So far, various methods of preparing 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives are described in the literature.
- EP-A-0678 503 ⁇ -amino- ⁇ -hydroxy- ⁇ -aryl-alkanecarboxamides are described, in particular in the claims and Examples, which exhibit renin-inhibiting properties and could be used as antihypertensive agents in pharmaceutical preparations.
- WO 02/02508 a multistep manufacturing process to obtain ⁇ -amino- ⁇ -hydroxy- ⁇ -aryl-alkanecarboxamides is described, in particular in the claims and Examples, in which the central intermediate is a 2,7-dialkyl-8-aryl-4-octenic acid or a 2,7-dialkyl-8-aryl-4-octenic acid ester.
- the double bond of this intermediate is simultaneously halogenated in the 4/5 position and hydroxylated in the 4-position via (under) halo-lactonisation conditions.
- the halolactone is converted to a hydroxy lactone and then the hydroxy group is converted to a leaving group, the leaving group is substituted with azide, the lactone amidated and then the azide is converted into the amine group.
- EP-A-1215201 an alternative route to obtain ⁇ -amino- ⁇ -hydroxy- ⁇ -aryl-alkanecarboxamides is disclosed, in particular in the claims and Examples.
- WO2006/131304 yet an alternative route to obtain ⁇ amino- ⁇ -hydroxy- ⁇ -aryl-alkanecarboxamides is disclosed using a pyrrolidine intermediate, in particular in the claims and Examples.
- C-8 lactam lactone compounds and more specifically 5-(5-oxo-tetrahydro-furan-2-yl)pyrrolidin-2-one compounds according to formula (I) as shown below, has been first described in WO2007/045420, in particular in the claims and Examples.
- the C-8 lactam lactone compounds are prepared using auxiliaries, such as the Evans auxiliary and azide chemistry to introduce the nitrogen atom.
- C-8 lactam lactone compounds in particular, a 5-(5-oxo-tetrahydro-furan-2-yl)pyrrolidin-2-one
- renin inhibitors in particular 2(5),4(5),5(5),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives
- 2(5),4(5),5(5),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives are obtainable in high diastereomeric and enantiomeric purity and in an economic manner using a novel approach by utilizing organocatalytic Michael and Henry reactions.
- the present invention provides methods to obtain a C-8 lactam lactone compound of formula (I)
- each R 1 is independently of one another hydrogen; C 1-7 alkyl, C 3-8 cycloalkyl or benzyl, in particular both R1 are branched C 3-6 alkyl such as isopropyl; and
- Act is an activating group selected from an amino protecting group, in particular one that together with N forms a carbamate; or a salt thereof;
- both R 1 are C 1-7 alkyl, preferably C 2-6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, isobutyl, or n-butyl; C 3-8 cycloalkyl such as cyclohexyl; or benzyl. Most preferably both R 1 are C 1-7 alkyl, in particular branched C 3-6 alkyl, such as isopropyl. In another embodiment, one or both of the R 1 are hydrogen.
- Act is an N-protecting group, for example, an amino protecting group which is conventionally used in peptide chemistry (cf.: “Protective groups in Organic Synthesis”, 5 th . Ed. T. W. Greene & P. G. M. Wuts, in particular in the relevant chapters thereof, especially in the chemistry of protecting pyrrolidines.
- Act serves as an activating group when present on the lactam nitrogen and that after lactam opening the Act group is a protecting group.
- Preferred protecting groups comprise, for example, (i) C 1 -C 4 -alkyl that is mono-, di- or trisubstituted by phenyl, such as benzyl, (or) benzhydryl or trityl, wherein the phenyl ring is unsubstituted or substituted by one or more, e.g. two or three, residues e.g.
- benzyloxycarbonyl Cbz
- 9-fluorenylmethyloxycarbonyl Fmoc
- benzyloxymethyl BOM
- pivaloyl-oxy-methyl POM
- trichloroethxoycarbonyl Troc
- 1-adamantyloxycarbonxyl Adoc
- the protecting group can also be silyl, like trialklysilyl, especially trimethylsilyl, tert.-butyl-dimethylsilyl, triethylsilyl, triisopropylsilyl, trimethylsilyethoxymethyl (SEM), and can also be substituted sulfonyl or substituted sulfenyl.
- Act examples include C 1-10 alkenyloxy carbonyl, C 8-10 aryl-C 1-6 alkyl, and C 1-6 alkyl-carbonyl, C 8-10 aryl-carbonyl, C 1-6 alkoxy-carbonyl, and C 8-10 aryl-C 1-6 alkoxycarbonyl.
- Act is C 8-10 aryl-C 1-6 alkoxycarbonyl, C 1-6 alkoxy-carbonyl, allyloxycarbonyl or C 6-10 aryl-C 1-6 alkyl such as benzyl, t-butoxycarbonyl or benzyloxycarbonyl.
- Act is t-butoxy- or benzyloxycarbonyl.
- the compound according to the formula (I) has the following stereochemistry:
- the compound of formula (I) has the following structure:
- a compound of the formula (I) may be used, inter alia, for the synthesis of pharmaceutically active substances, preferably renin inhibitors such as aliskiren, especially as described in WO2007/045420, in particular in the claims and Examples.
- the compound of formula (I) has preferably one of the following structures:
- methods to obtain a C-8 lactam lactone compound of formula (I) provide compounds having one of the following structures:
- Act is an activating group selected from an amino protecting group, in particular one that together with N forms a carbamate.
- methods to obtain a C-8 lactam lactone compound of formula (I) provide compounds having one of the following structures:
- R1 is hydrogen, C 1-7 alkyl, C 3-8 cycloalkyl or benzyl and Act is an activating group selected from an amino protecting group, in particular one that together with N forms a carbamate.
- methods to obtain a C-8 lactam lactone compound of formula (I) provide compounds having one of the following structures:
- R1 is hydrogen, C 1-7 alkyl, C 3-8 cycloalkyl or benzyl and Act is an activating group selected from an amino protecting group, in particular one that together with N forms a carbamate.
- the present invention relates to a method for preparing a compound of IV),
- R1 is hydrogen, C 1-7 alkyl or C 3-8 cycloalkyl; R2 and R3 together with N form a chiral amine moiety; or a salt thereof said process comprising subjecting a compound of formula (II)
- R1 is as defined for a compound of formula (IV), or a salt thereof, to a chiral amine of formula (III)
- R2 and R3 are as defined for a compound of formula (IV), or a salt thereof, to form the enamine moiety. This process step as such, also forms an embodiment of the invention.
- R 1 can be taken from the definitions for compounds of formula (I).
- the compound of formula (II) is isovaleryl aldehyde.
- the amine of formula (III) is a chiral amine, in particular a pyrrolidine derived catalyst suitable for asymmetric Michael addition reactions.
- a pyrrolidine derived catalyst suitable for asymmetric Michael addition reactions examples include those exemplified in the sketches below.
- R1 is hydrogen, C 1-7 alkyl, such as C 2-7 alkyl, C 3-8 cycloalkyl or benzyl, in particular C 1-7 alkyl, such as C 2-7 alkyl, C 3-8 cycloalkyl or benzyl; R2 and R3 together with N form a chiral amine moiety; or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
- R1, R2 and R3, including the preferred ones, are as defined for compounds of formulae (I) and (III), respectively.
- R1 is preferably isopropyl.
- the compound of formula (IV) has a structure according to formula (IVa),
- R4 is carboxy, amido, N (mono- or di-unsubstituted or substituted C 2-7 alkyl) amido, unsubstituted or substituted C 1-7 alkyl or tetrazolyl; or a salt thereof.
- the compound of formula (IV) has a structure according to (IVb)
- R9 is independently of one another C 1-9 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, or phenyl, preferred is that at least one of the R9 is larger than methyl, such as tert-butyl.
- the enamine of formula (IV) can be isolated or formed in situ and be directly reacted on in the organocatalytic nitro-Michael addition reaction.
- the enamine is formed in situ without isolation.
- the present invention also relates as a further step or as an individual to a process for preparing a compound of formula (V),
- R1 is as defined for a compound of formula (I), or a salt thereof, said process comprising an organocatalytic nitro-Michael addition reaction of nitroethylene or a precursor thereof with a compound of formula (IV) as defined above.
- this reaction takes place by directly reacting the compounds of formulae (II) and (III) as defined above with the nitroethylene or the precursor thereof without isolating the enamine of formula (IV).
- R1, R2 and R3, including the preferred ones, are as defined for compounds of formulae (I) and (III), respectively.
- the nitroethylene is prepared in situ so that a precursor of nitroethylene is added in the organocatalytic nitro-Michael addition reaction.
- the precursor of nitroethylene has a structure of formula (XII)
- —O-LG is a leaving group that is eliminated under the reaction conditions to reveal the nitroethylene.
- LG are C 1-7 alkylcarbonyl, such as methylcarbonyl, arylcarbonyl, such as phenylcarbonyl, phthaloyl, or C 1-7 alkyl- or arylsulfonyl, such as methansulfonyl and toluolsulfonyl.
- the precursor is particularly preferably 2-nitroethyl benzoate.
- the precursors of formula (XII) can be prepared as known in the art, e.g. by esterification of the respective acid or acid chloride with 2-nitroethanol. Procedures are described e.g. in J. F. W.
- LG is C 1-7 alkylcarbonyl or arylcarbonyl
- organocatalytic nitroethylene Michael addition reaction under conditions that eliminate the ester moiety, such as basic conditions, using in particular mild bases such as organic bases, in particular N-containing bases such as N-methyl morpholine or N-ethyl morpholine.
- the nitroethylene and the chiral enamine of Formula (IV) react with each other in a stereoselective manner which is driven either by “steric shielding” or by “electronic shielding” due to the chirality of the enamine.
- the stereochemical outcome of the reaction depends on the chirality of the chiral amine of formula (III), the organo catalyst, (R) or (S) and the corresponding “steric- or electronic shielding”.
- the chiral amine of formula (III) is recycled and can be used again in the reaction with the aldehyde of formula (II).
- a preferred amount of the catalyst ranges from 0.5 to 20 mol %, such as 1 to 15 mol %, in particular 5 to 10 mol %.
- the organocatalysis cycle is illustrated in Scheme I.
- R1 is hydrogen, C 1-7 alkyl, such as C 2-7 alkyl, C 3-8 cycloalkyl or benzyl, in particular C 1-7 alkyl, such as C 2-7 alkyl, C 3-8 cycloalkyl or benzyl; or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
- R1 is preferably isopropyl.
- this synthesis comprises as a further step or as an individual synthesis the process for preparing a compound of formula (VI),
- R1 is as defined for a compound of formula (I), or a salt thereof, said process comprising the reduction of the aldehyde carbonyl functionality of the compound of formula (V).
- the reduction to an alcohol is well known to a person skilled in the art and is described e.g. in Methoden der organischen Chemie” ( Methods of Organic Chemistry ), Houben Weyl, 4th edition, Volume IV/c, Reduction I & II. Georg Thieme Verlag, Stuttgart 1974, in particular in the relevant chapters thereof.
- the reduction typically takes place in the presence of a suitable reducing agent selected from LSelectride, Lithium trialkoxyaluminium hydrides, for example, lithium tri-tert-butyloxy aluminium hydride, lithium triethylborohydride, tetraalkylammoniumborohydrides and NaBH 4 or by addition of a Lewis acid like CeCl 3 to the NaBH 4 .
- a preferred example of the reagent is NaBH 4 due to its selectivity.
- the reduction takes place preferably in an inert solvent, more preferably in tetrahydrofuran or toluene or in mixtures of THF/water or ethanol/water.
- the reaction time and the temperature are chosen so as to bring the reaction to completion at a minimum time without the production of unwanted side products.
- the reaction can be conducted at 0° C. to reflux, preferably 10 to 80° C., more preferably 15 to 40° C., such as 20-25° C., for 1 min to 3 h, preferably 10 min to 2 h, most preferably 20 min to 2 h.
- the reaction is carried out following the conversion to a compound of formula (V), it is possible and preferred that the compound of formula (V) is reduced without isolating it. It is therefore an option to perform the reduction step, preferably together with the aforementioned organocatalytic nitro-Michael addition reaction, in a continuous flow manner. In such a case the reduction is preferably carried out under continuous flow catalytic conditions.
- the reduction is preferably carried out under continuous flow catalytic conditions.
- R1 is hydrogen, C 1-7 alkyl, such as C 2-7 alkyl, C 3-8 cycloalkyl or benzyl, in particular C 1-7 alkyl, such as C 2-7 alkyl, C 3-8 cycloalkyl or benzyl; or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
- R1 is preferably isopropyl.
- nitroalcohol of formula (VI) is one of the possible starting materials for the nitro-aldol (Henry) reaction which will be described later.
- the other reagent, the aldehyde of formula (VIII) as described below, can be prepared as shown below or as described in the examples.
- a compound of formula (VI) as the starting material for the aldehyde, it can be the same compound of formula (VI) (same R1) as the reagent for the nitro-aldol reaction, or different compounds of formula (VI) can be used for the preparation of the aldehyde on the one hand and as the starting material for the nitro-aldol reaction on the other hand.
- this synthesis comprises as a further step or as an individual synthesis process for preparing a compound of formula (VII)
- R1 is as defined for a compound of formula (I) and PG is a hydroxyl protecting group, or a salt thereof, said process comprising an protecting the hydroxyl functionality of the compound of formula (VI) as defined above with a protecting group.
- Typical procedures to protect the hydroxyl functionality can be taken from the literature references cited in the section “General process conditions” below in connection with protecting groups.
- PG is a benzyl group since this group can be removed selectively and conveniently by hydrogenation.
- Other preferred examples of protecting groups are e.g., p-methoxybenzyl, o,m,p-pyridylmethyl and silyl protecting groups as mentioned in the references cited in the section “General process conditions” below, in particular TMS, TES, TIPS and TBDMS.
- R1 is as defined for a compound of formula (I) and PG is a hydroxyl protecting group, or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
- R1 and PG are as defined for compounds of formulae (I) and as described above, respectively.
- R1 is preferably isopropyl.
- PG is preferably benzyl.
- this synthesis comprises as a further step or as an individual synthesis the process for preparing a compound of formula (VIII),
- R1 is as defined for a compound of formula (I) and PG is as defined for a compound of formula (VII), or a salt thereof, said process comprising a Nef reaction of the compound of formula (VII) as defined above to convert the nitro functionality to an aldehyde functionality.
- R1 is as defined for a compound of formula (I) and PG is a hydroxyl protecting group, or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
- R1 and PG are as defined for compounds of formulae (I) and as described above, respectively.
- R1 is preferably isopropyl.
- PG is preferably benzyl.
- the compound of formula (VIII) can be prepared by using a chloride compound of formula (XIII) and reacting with cyanide to form the corresponding nitrile of formula (XIV) and reducing the nitrile to obtain the aldehyde of formula (VIII).
- this synthesis comprises as a further step or as an individual synthesis the process for preparing a compound of formula (XIV),
- R1 is as defined for a compound of formula (I) and PG is as defined for a compound of formula (VII), or a salt thereof, said process comprising reacting a compound of formula (XIII)
- R1 is as defined for a compound of formula (I) and PG is as defined for a compound of formula (VII) and X is a halogen, or a salt thereof, with a source of CN ⁇ to convert the chloride functionality to a nitrile functionality.
- X is a halogen such as chlorine, bromine or iodine, preferably chlorine.
- substitution of a halogen to a nitrile is well known to a person skilled in the art and is described e.g. in Organikum, 20 th ed, Wiley VCH, p. 245-247, and literature cited therein.
- the substitution typically takes place in the presence of a CN ⁇ source selected from metal cyanides, for example, NaCN, LiCN, KCN or N(C 1-7 alkyl) 4 CN.
- a preferred example of the reagent is NaCN.
- the reaction takes place preferably in an inert solvent, more preferably in DMSO, DMF, NMP, glyme, diglyme or tetrahydrofuran.
- reaction time and the temperature are chosen so as to bring the reaction to completion at a minimum time without the production of unwanted side products.
- the reaction can be conducted at 0° C. to reflux, preferably 10 to 120° C., more preferably 20 to 100° C., such as 50-90° C., for 1 h to 5 h, preferably 2 min to 3 h, most preferably 3 h.
- R1 is as defined for a compound of formula (I) and PG is a hydroxyl protecting group, or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
- R1 and PG are as defined for compounds of formulae (I) and as described above, respectively.
- R1 is preferably isopropyl.
- PG is preferably benzyl.
- this synthesis comprises as a further step or as an individual synthesis the process for preparing a compound of formula (VIII),
- R1 is as defined for a compound of formula (I) and PG is as defined for a compound of formula (VII), or a salt thereof, said process reduction of the nitrile functionality of a compound of formula (XIV) as defined above to convert the nitrile functionality to an aldehyde functionality.
- the reduction of a nitrile to an aldehyde is well known to a person skilled in the art and is described e.g. in J. Organic Chemistry, 24, 627 (1959), J. Organic Chemistry, 46, 5250 (1981) and Tetrahedron Letters, 32, 4115 (1991).
- the reduction typically takes place in the presence of an H ⁇ source selected from hydrides, for example, DIBAH.
- a preferred example of the reagent is DIBAH.
- the reaction takes place preferably in an inert solvent, more preferably in dichloromethane, hexane, heptane, cyclohexane toluene or tetrahydrofuran or mixtures of these.
- reaction time and the temperature are chosen so as to bring the reaction to completion at a minimum time without the production of unwanted side products.
- the reaction can be conducted at ⁇ 20° C. to reflux, preferably ⁇ 10 to 50° C., more preferably ⁇ 5 to 30° C., such as 0° C., for 30 min to 5 h, preferably 1 min to 3 h, most preferably 2 h.
- the aldehyde of formula (VIII) is a starting material for the nitro-aldol reaction.
- this synthesis comprises as a further step or as an individual synthesis the process for preparing a compound of formula (IX),
- both R1's are the same or different from each other and are as defined for a compound of formula (I)
- R5 is hydrogen or PG
- PG is as defined for a compound of formula (VII), whereby both PG's can be the same or different, or a salt thereof, said process comprising a nitro-aldol (Henry) reaction of the nitro compound of formula (VI) as defined above, when R5 is H, or the O-protected nitro compound of formula (VII) as defined above, when R5 is PG, together with the aldehyde of formula (VIII) as defined above.
- Henry nitro-aldol
- the reagents are the aldehyde of formula (VIII) and the nitro compound of formula (VI) to obtain a compound of formula (IX) wherein R5 is H.
- the reagents are the aldehyde of formula (VIII) and the O-protected nitro compound of formula (VII) to obtain a compound of formula (IX) wherein R5 is PG, whereby both PG's in the compound of formula (IX) are preferably the same so that they can be removed in a single step.
- PG is in this case benzyl.
- the R1's can be the same or different. Preferably, they are the same and as defined herein, e.g. they are both isopropyl.
- organocatalysts or chiral metal ligand complexes, e.g. Shibasaki system, Evans system or Trost system [see cited literature in references 1.), 2.) and 5.)].
- Shibasaki system see reference 8
- the Nagasawa system see reference 7
- the organocatalyst is a chiral amine, for example sparteine.
- both R1's are the same or different from each other and are hydrogen, C 1-7 alkyl, such as C 2-7 alkyl, C 3-8 cycloalkyl or benzyl, in particular C 1-7 alkyl, such as C 2-7 alkyl, C 3-8 cycloalkyl or benzyl;
- R5 is hydrogen or PG;
- PG is a hydroxyl protecting group and whereby both PG's can be the same or different; or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
- R1 and PG are as defined for compounds of formulae (I) and as described above, respectively.
- R1 is preferably isopropyl.
- PG is preferably benzyl. It is also preferred that both R1's are the same. It is also preferred that if both PG's are present they are the same.
- R5 is hydrogen.
- R1 and PG are as defined herein.
- the stereo selectivity at the hydroxyl function can be controlled by using the appropriate catalyst as described in the above literature references.
- this synthesis comprises as a further step or as an individual synthesis the process for preparing a compound of formula (X),
- both R1's are the same or different from each other and are as defined for a compound of formula (I), and Act is an activating group selected from an amino protecting group, in particular one that together with N forms a carbamate, or a salt thereof, said process comprising hydrogenation of the nitro functionality of the compound of formula (IX).
- Hydrogenation typically takes place in the presence of a catalyst selected from a heterogeneous catalyst or a homogeneous catalyst, such as Wilkinson's catalyst, preferably a heterogeneous catalyst.
- a catalyst selected from a heterogeneous catalyst or a homogeneous catalyst, such as Wilkinson's catalyst, preferably a heterogeneous catalyst.
- the catalyst include Raney nickel, palladium/C, Pd(OH) 2 (Perlman's catalyst), nickel boride, platinum metal or platinum metal oxide, rhodium, ruthenium and zinc oxide, more preferably Raney nickel, palladium/C, platinum metal or platinum metal oxide, most preferably palladium/C or Raney nickel.
- the catalyst is preferably used in an amount of 1 to 20%, more preferably 5 to 10%.
- the reaction can be conducted at atmospheric or elevated pressure, such as a pressure of 2-10 bar, e.g.
- the reaction is conducted at atmospheric pressure.
- the hydrogenation takes place preferably in an inert solvent, more preferably in tetrahydrofuran or toluene.
- protic solvents such as alcohol, e.g. ethanol or methanol, or ethyl acetate. These solvents may be used in the presence of water.
- the reaction time and the temperature are chosen so as to bring the reaction to completion at a minimum time without the production of unwanted side products. Typically the reaction can be conducted at 0° C.
- to reflux preferably 0 to 60° C., such as 0 to 40° C., more preferably 15-30° C., such as room temperature, for 10 min to 12 h, preferably 20 min to 6 h, most preferably 30 min to 4 h, such as 1 to 3 h or 6 to 12 h.
- the removal of the protecting group(s) PG is conducted concomitantly. This can be achieved if the protecting group(s) PG are selected from e.g. benzyl groups. Alternatively, the protecting group(s) PG can be removed as a separate step by methods well known in the art and as described herein, in particular the literature references cited in the section “General process conditions” below in connection with protecting groups, to reveal the hydroxyl functionality.
- the introduction of the activating group Act is conducted concomitantly. This can be achieved by using the reagent, e.g. as a solvent or co-solvent, in the hydrogenation reaction. This is particularly appropriate if Act is an alkoxy carbonyl group so as to form, together with N, a carbamate, where the corresponding alkoxy carbonyl anhydride, e.g. BOC anhydride, can be present in the hydrogenation reaction either stoichiometrically or in excess. Reaction conditions can be the same as described below.
- the group Act can be introduced in a separate step by methods well known in the art and as described herein, in particular the literature references cited in the section “General process conditions” below in connection with protecting groups, to protect the amine functionality.
- this conversion proceeds under standard conditions and as described e.g. in standard reference works, such as J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J.
- the reaction is preferably conducted under basic conditions.
- the base can be used stoichiometrically or catalytically.
- Suitable bases include organic or inorganic bases, preferably organic bases, more preferably a nitrogen base, yet more preferably a tertiary nitrogen base.
- examples of the tertiary nitrogen base include triethylamine, diisopropylethylamine, DBU, TMEDA and trimethylamine.
- DMAP can be used as a catalyst.
- the reaction can be conducted in any suitable solvent, preferably a polar solvent such as an ethyl acetate or isopropyl acetate, an ether, such as THF or TBME, an alcohol, such as methanol, ethanol or isopropanol, or a halogenated solvent, more preferably THF, methylene chloride or isopropyl acetate.
- a polar solvent such as an ethyl acetate or isopropyl acetate
- an ether such as THF or TBME
- an alcohol such as methanol, ethanol or isopropanol
- a halogenated solvent more preferably THF, methylene chloride or isopropyl acetate.
- to reflux preferably 0 to 60° C., more preferably 15-50° C., such as 20-45° C., for 10 min to 36 h, preferably 3 h to 24 h, most preferably 6 h to 24 h, such as 12-17 h.
- the compound of formula (X) is obtained in a one-pot synthesis from a compound of formula (IX) using hydrogenation in the presence of (Act) 2 O, such as (Boc) 2 0.
- R1's are the same or different from each other and are hydrogen, C 1-7 alkyl, such as C 2-7 alkyl, C 3-8 cycloalkyl or benzyl, in particular C 1-7 alkyl, such as C 2-7 alkyl, C 3-8 cycloalkyl or benzyl; and
- Act is an activating group selected from an amino protecting group, in particular one that together with N forms a carbamate;
- R1 and Act are as defined for compounds of formula (I).
- R1 is preferably isopropyl.
- Act is preferably alkoxy carbonyl, in particular butoxy carbonyl (BOC). It is also preferred that both R1's are the same.
- the compounds of formula (X) have preferably the structure of formula (Xa)
- this synthesis comprises as a further step or as an individual synthesis the process for preparing a compound of formula (I),
- R1 and Act are as defined above, or a salt thereof, said process comprising selective oxidation of the primary alcohols of the compound of formula (X) as defined above to effect double ring closure into the lactone lactam.
- the selective oxidation of the primary alcohol preferably takes place under conditions so as to keep the other functionalities on the molecule intact, in particular the secondary alcohol but also the Act group. Selectivity is generally achieved due to the lower reactivity of the secondary alcohol
- Suitable oxidants are mild oxidants that avoid over-oxidation, in particular mild oxidative systems using a catalyst are preferred. Such a system is e.g.
- N-methyl morpholine N-oxide together with tetrapropyl ammonium perruthenate (TPAP) as the catalyst. It is preferred that the oxidant is used in excess to ensure good conversion rates.
- the catalyst is typically employed in an amount of 1 to 20 mol %, such as 5 to 10 mol %. Due to the position of the amine and the secondary alcohol in the molecule, spontaneous cyclization to form the lactam and the lactone, respectively, occurs. The cyclization is in equilibrium with the ring opening, so that removal of the water formed during the ring closure is preferred to drive the equilibrium towards the lactone lactam. The removal of water can be achieved by entrapment in a Dean Stark apparatus, if reflux conditions are used, or in general by placing molecular sieves in the reaction mixture.
- the aldehyde compound of formula (VIII) can be reacted with a nitroester followed by hydrogenation and oxidation.
- this synthesis comprises as a further step or as an individual synthesis the process for preparing a compound of formula (XVI),
- R1's are the same or different from each other and are as defined for a compound of formula (I), R8 is C 1-7 alkyl, and PG is as defined for a compound of formula (VII), or a salt thereof, said process comprising a nitro-aldol (Henry) reaction of the nitro compound of formula (XV)
- R8 is C 1-7 alkyl
- R1 is as defined for a compound of formula (IV)
- PG is a hydroxyl protecting group, or a salt thereof, together with the aldehyde of formula (VIII) as defined above.
- R8 is C 1-4 alkyl, in particular methyl or ethyl, specifically methyl.
- R1 is hydrogen, C 1-7 alkyl, C 3-8 cycloalkyl or benzyl, in particular C 1-7 alkyl or hydrogen, in particular hydrogen.
- R1 and PG in compound of formula (XVI), including the preferred ones, are as defined for compounds of formulae (I) and as described above, respectively.
- R1 is preferably isopropyl.
- PG is preferably benzyl.
- reaction conditions are analogous to the ones provided for the preparation of compounds of formula (IX) as described above.
- both R1's are the same or different from each other and are hydrogen, C 1-7 alkyl, C 3-8 cycloalkyl or benzyl, in particular hydrogen or C 1-7 alkyl;
- R8 is C 1-7 alkyl;
- PG is a hydroxyl protecting group; or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
- R1 is preferably hydrogen or isopropyl.
- PG is preferably benzyl. It is also preferred that both R1's are the same. Alternatively, one is hydrogen and the other is isopropyl. Most preferably, R8 is methyl.
- the compounds of formula (XVI) have preferably the structure of formula (XVIa)
- R1, R8 and PG are as defined herein.
- the stereo selectivity at the hydroxyl function can be controlled by using the appropriate catalyst as described in the above literature references.
- this synthesis comprises as a further step or as an individual synthesis the process for preparing a compound of formula (XVII),
- both R1's are the same or different from each other and are as defined for a compound of formula (I), or a salt thereof, said process comprising hydrogenation of the nitro functionality of the compound of formula (XVI) and ring closure to form the lactam, said process, comprising as a concomitant or separate step the removal of the protecting group PG to reveal the hydroxyl functionality.
- the removal of the protecting group PG in a compound of formula (XVI) is conducted concomitantly. This can be achieved if the protecting group(s) PG are selected from e.g. benzyl groups. Alternatively, if PG is benzyl, the two hydrogenation reactions can be conducted as separate steps.
- the protecting group PG in particular if other than benzyl, can be removed as a separate step by methods well known in the art and as described herein, in particular the literature references cited in the section “General process conditions” below in connection with protecting groups, to reveal the hydroxyl functionality.
- both R1's are the same or different from each other and are hydrogen, C 1-7 alkyl, such as C 2-7 alkyl, C 3-8 cycloalkyl or benzyl; or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
- R1 is preferably hydrogen or isopropyl. It is also preferred that both R1's are the same or one is hydrogen and the other is isopropyl.
- the compounds of formula (XVII) have preferably the structure of formula (XVIIa),
- this synthesis comprises as a further step or as an individual synthesis the process for preparing a compound of formula (XVIII),
- R1 are as defined above, or a salt thereof, said process comprising selective oxidation of the primary alcohol of the compound of formula (XVII) as defined above to effect ring closure into the lactone lactam.
- the compound of formula (XVIII) has preferably one of the following structures:
- methods to obtain a C-8 lactam lactone compound of formula (XVIII) provide compounds having one of the following structures:
- Act is an activating group selected from an amino protecting group, in particular one that together with N forms a carbamate.
- methods to obtain a C-8 lactam lactone compound of formula (XVIII) provide compounds having one of the following structures:
- R1 is hydrogen, C 1-7 alkyl, C 3-8 cycloalkyl or benzyl and Act is an activating group selected from an amino protecting group, in particular one that together with N forms a carbamate.
- methods to obtain a C-8 lactam lactone compound of formula (XVIII) provide compounds having one of the following structures:
- R1 is hydrogen, C 1-7 alkyl, C 3-8 cycloalkyl or benzyl and Act is an activating group selected from an amino protecting group, in particular one that together with N forms a carbamate.
- Each of the above mentioned method steps can be used individually in a method to prepare renin inhibitors such as aliskiren.
- the steps are used in combination of one or more, most preferably all, to prepare renin inhibitors such as aliskiren.
- a lactam lactone of formula (I) can be converted to aliskiren as described, e.g. in WO2007/045420, in particular in the claims and Examples.
- the present invention relates to a process for preparing a compound of formula (XI)
- R1 is as defined for a compound of formula (I)
- R6 is halogen, hydroxyl, C 1-6 halogenalkyl, C 1-6 alkoxy-C 1-6 alkyloxy or C 1-6 alkoxy-C 1-6 alkyl
- R7 is halogen, hydroxyl, C 1-4 alkyl or C 1-4 alkoxy, or a salt thereof, comprising one or more of the following steps either individually or in any combination:
- the compound of formula (XI) is aliskiren.
- Alkyl being a radical or part of a radical is a straight or branch (one or, if desired and possible, more times) carbon chain, and is especially C 1 -C 7 -alkyl, such as C 1 -C 4 -alkyl, in particular branched C 1 -C 4 -alkyl, such as isopropyl.
- the term “lower” or “C 1 -C 7 -” defines a moiety with up to and including maximally 7, especially up to and including maximally 4, carbon atoms, said moiety being branched (one or more times) or straight-chained and bound via a terminal or a non-terminal carbon.
- Lower or C 1 -C 7 -alkyl for example, is n-pentyl, n-hexyl or n-heptyl or preferably C 1 -C 4 -alkyl, especially as methyl, ethyl, n-propyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, in particular methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl. Very preferred is iso-propyl.
- Alkyl preferably has up to 20 carbon atom and is more preferably C 1 -C 7 -alkyl. Alkyl is straight-chained or branched (one or, if desired and possible, more times). Very preferred is methyl.
- Halo or halogen is preferably fluoro, chloro, bromo or iodo, most preferably fluoro, chloro or bromo; where halo is mentioned, this can mean that one or more (e.g. up to three) halogen atoms are present, e.g. in halo-C 1 -C 7 -alkyl, such as trifluoromethyl, 2,2-difluoroethyl or 2,2,2-trifluoroethyl.
- Halogenalkyl may be linear or branched and preferably comprise 1 to 4 C atoms, especially 1 or 2 C atoms. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.
- Branched alkyl preferably comprises 3 to 6 C atoms. Examples are i-propyl, i- and t-butyl, and branched isomers of pentyl and hexyl. Branched C 1 -C 4 -alkyl is preferred, such as isopropyl.
- Cycloalkyl preferably comprises 3 to 8 ring-carbon atoms, 3 or 5 being especially preferred. Some examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl.
- the cycloalkyl may optionally be substituted by one or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, thiol, alkylthio, nitro and cyano.
- Alkenyl may be linear or branched alkyl containing a double bond and comprising preferably 2 to 12 C atoms, 2 to 8 C atoms being especially preferred. Particularly preferred is a linear C 2-4 alkenyl.
- alkyl groups are ethyl and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octacyl and eicosyl, each of which containing a double bond.
- allyl is preferably allyl.
- Alkylene is a bivalent radical derived from C 1-7 alkyl and is especially C 2 -C 7 -alkylene or C 2 -C 7 -alkylene which is interrupted by, one or more, O, NR14 or S, wherein R14 is alkyl, each of which can be unsubstituted or substituted, by one or more substituents independently selected from for example, C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl or C 1 -C 7 -alkoxy.
- Alkenylene is a bivalent radical derived from C 2-7 alkenyl and can be interrupted by, one or more, O, NR14 or S, wherein R14 is alkyl, and is unsubstituted or substituted by one or more, e.g. up to three, substitutents preferably independently selected from the substitutents mentioned above for alkylene.
- Alkylamino and dialkylamino may be linear or branched. Some examples are methylamino, dimethylamino, ethylamino, and diethylamino.
- Sulfonyl is (unsubstituted or substituted) C 1 -C 7 -alkylsulfonyl, such as methylsulfonyl, (unsubstituted or substituted) phenyl- or naphthyl-C 1 -C 7 -alkylsulfonyl, such as phenyl-methanesulfonyl, or (unsubstituted or substituted) phenyl- or naphthyl-sulfonyl; wherein if more than one substituent is present, e.g.
- the substituents are selected independently from cyano, halo, halo-C 1 -C 7 alkyl, halo-C 1 -C 7 -alkyloxy- and C 1 -C 7 -alkyloxy.
- C 1 -C 7 -alkylsulfonyl such as methylsulfonyl
- (phenyl- or naphthyl)-C 1 -C 7 -alkylsulfonyl such as phenylmethanesulfonyl.
- Sulfenyl is (unsubstituted or substituted) C 6-10 aryl-C 1 -C 7 -alkylsulfenyl or (unsubstituted or substituted) C 6-10 arylsulfenyl, wherein if more than one substituent is present, e.g. one to four substitutents, the substituents are selected independently from nitro, halo, halo-C 1 -C 7 alkyl and C 1 -C 7 -alkyloxy.
- Alkoxy-alkyloxy may be linear or branched.
- the alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyloxy group preferably comprises 1 to 4 C atoms.
- Examples are methoxymethyloxy, 2-methoxyethyloxy, 3-methoxypropyloxy, 4-methoxybutyloxy, 5-methoxypentyloxy, 6-methoxyhexyloxy, ethoxymethyloxy, 2-ethoxyethyloxy, 3-ethoxypropyloxy, 4-ethoxybutyloxy, 5-ethoxypentyloxy, 6-ethoxyhexyloxy, propyloxymethyloxy, butyloxymethyloxy, 2-propyloxyethyloxy and 2-butyloxyethyloxy.
- Alkoxyalkyl may be linear or branched.
- the alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyl group preferably comprises 1 to 4 C atoms.
- Examples are methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl, 6-methoxyhexyl, ethoxymethyl, 2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5-ethoxypentyl, 6-ethoxyhexyl, propyloxymethyl, butyloxymethyl, 2-propyloxyethyl and 2-butyloxyethyl.
- Alkoxy being a radical or part of a radical is, for example, C 1 -C 7 -alkoxy and is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy and also includes corresponding pentyloxy, hexyloxy and heptyloxy radicals.
- C 1 -C 4 alkoxy is preferred.
- Alkoxy may be linear or branched and preferably comprise 1 to 4 C atoms. Examples are methoxy, ethoxy, n- and i-propyloxy, n-, i- and t-butyloxy, pentyloxy and hexyloxy.
- Alkanoyl is, for example, C 2 -C 8 -alkanoyl and is, for example, acetyl [—C( ⁇ O)Me], propionyl, butyryl, isobutyryl or pivaloyl.
- C 2 -C 5 -Alkanoyl is preferred, especially acetyl.
- Acetyl is —C( ⁇ O)C 1 -C 7 alkyl, preferably —C( ⁇ O)Me.
- Protecting groups may be present (see also under “General Process Conditions”) and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove and hereinafter.
- two or more protecting groups are present in one intermediate mentioned herein, they are chosen so that, if one of the groups needs to be removed, this can be done selectively, e.g. using two or more different protecting groups that are cleavable under different conditions, e.g. one class by mild hydrolysis, the other by hydrolysis under harder conditions, one class by hydrolysis in the presence of an acid, the other by hydrolysis in the presence of a base, or one class by reductive cleavage (e.g. by catalytic hydrogenation), the other by hydrolysis, or the like.
- two or more protecting groups that are cleavable under different conditions, e.g. one class by mild hydrolysis, the other by hydrolysis under harder conditions, one class by hydrolysis in the presence of an acid, the other by hydrolysis in the presence of a base, or one class by reductive cleavage (e.g. by catalytic hydrogenation), the other by hydrolysis, or the like.
- a hydroxyl protecting group any group that is appropriate for reversible protection of hydroxy groups is possible, e.g. those mentioned in the standard textbooks under “General Process Conditions”.
- a hydroxyl protecting group may, just to mention a few examples, be selected from a group comprising (especially consisting of) a silyl protecting group, especially diary)-lower alkyl-silyl, such as diphenyl-tert-butylsilyl, or more preferably tri-lower alkylsilyl, such as tert-butyldimethylsilyl or trimethylsilyl; an acyl group, e.g.
- lower alkanoyl such as acetyl; benzoyl; lower alkoxycarbonyl, such as tert-butoxycarbonyl (Boc), or phenyl-lower alk-oxycarbonyl, such as benzyloxycarbonyl; tetrahydropyranyl; unsubstituted or substituted 1-phenyl-lower alkyl, such as benzyl or p-methoxybenzyl, and methoxymethyl.
- Boc selectively removable by hydrolysis
- benzyl selectively removable by hydrogenation
- Silyl is —SiRR′R′′, wherein R, R′ and R′′ are independently of each other C 1-7 alkyl, aryl or
- amino protecting group any group that is appropriate for reversible protection of hydroxy groups is possible, e.g. those mentioned in the standard textbooks under “General Process Conditions”.
- An amino protecting group may, just to mention a few examples, be selected from a group comprising (especially consisting of) acyl (especially the residue of an organic carbonic acid bound via its carbonyl group or an organic sulfonic acid bound via its sulfonyl group), arylmethyl, etherified mercapto, 2-acyl-lower alk-1-enyl, silyl or N-lower alkylpyr-rolidinylidene.
- Preferred amino-protecting groups are lower alkoxycarbonyl, especially tert-butoxycarbonyl (Boc), phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, fluorenyl—lower alkoxycarbonyl, such as fluorenylmethoxycarbonyl, 2-lower alkanoyl-lower alk-1-en-2-yl and lower alkoxycarbonyl-lower alk-1-en-2-yl, with most preference being given to isobutyryl, benzoyl, phenoxyacetyl, 4-tert-butylphenoxyacetyl, N,N-dimethylformamidinyl, N-methylpyrrolidin-2-ylidene or especially tert-butoxycarbonyl.
- phenyl-lower alkoxycarbonyl such as benzyloxycarbonyl
- fluorenyl—lower alkoxycarbonyl such as fluorenylmethoxy
- nitrogen protecting groups are acetyl, benzyl, cumyl, benzhydryl, trityl, benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbony (Fmoc), benzyloxymethyl (BOM), pivaloyl-oxy-methyl (POM), trichloroethxoycarbonyl (Troc), 1-adamantyloxycarbonyl (Adoc), allyl, allyloxycarbonyl, trimethylsilyl, tert.-butyl-dimethylsilyl, triethylsilyl (TES), triisopropylsilyl, trimethylsilyethoxymethyl (SEM), t-butoxycarbonyl (BOC), t-butyl, 1-methyl-1,1-dimethylbenzyl, (phenyl)methylbenzene, pyrridinyl and pivaloyl.
- nitrogen protecting groups are acetyl, benzyl, benzyloxycarbonyl (Cbz), triethylsilyl (TES), trimethylsilyethoxymethyl (SEM), t-butoxycarbonyl (BOC), pyrrolidinylmethyl and pivaloyl.
- Further nitrogen protecting groups are pivaloyl, pyrrolidinylmethyl, t-butoxycarbonyl, benzyl and silyl groups, particularly silyl groups according to the formula SiR7R8R9, wherein R7, R8 and R9 are, independently of each other, alkyl or aryl.
- Preferred examples for R7, R8 and R9 are methyl, ethyl, isopropyl, t-butyl and phenyl.
- carboxylate is to be understood as an ester group —CO 2 R attached on N, wherein R is, for example, alkyl, aryl or arylalkyl, as defined herein.
- Unsubstituted or substituted aryl being a radical or part of a radical, is preferably a mono- or polycyclic, especially monocyclic, bicyclic or tricyclic aryl moiety with 6 to 22 carbon atoms, especially phenyl (very preferred), naphthyl (very preferred), indenyl, fluorenyl, acenapthylenyl, phenylenyl or phenanthryl, and is unsubstituted or substituted by one or more, especially one to three, moieties, preferably independently selected from the group consisting of C 1 -C 7 -alkyl, C 1 -C 7 -alkynyl, halo-C 1 -C 7 -alkyl, such as trifluoromethyl, halo, especially fluoro, chloro, bromo or iodo, hydroxy, C 1 -C 7 -alkoxy, phenyloxy, naphthyloxy, phenyl
- Aryloxy refers to a Aryl-O— wherein aryl is as defined above.
- Unsubstituted or substituted heterocyclyl is a mono- or polycyclic, preferably a mono-, bi- or tricyclic-, most preferably mono-, unsaturated, partially saturated, saturated or aromatic ring system with preferably 3 to 14 (more preferably 5 to 14) ring atoms and with one or more, preferably one to four, heteroatoms independently selected from nitrogen, oxygen, sulfur, S( ⁇ O)— or S—( ⁇ O) 2 , and is unsubstituted or substituted by one or more, e.g.
- substitutents preferably independently selected from the Preferred substituents are selected from the group consisting of halo, C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkoxy, such as trifluoromethoxy and C 1 -C 7 -alkoxy-C 1 -C 7 -alkoxy.
- the heterocyclyl is an aromatic ring system, it is also referred to as heteroaryl.
- the compounds described in the present invention can be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
- the compounds of the present invention can possess one or more asymmetric centers.
- the preferred absolute configurations are as indicated herein specifically. However, any possible pure enantiomer, pure diastereoisomer, or mixtures thereof, e.g., mixtures of enantiomers, such as racemates, are encompassed by the present invention.
- Salts are especially the pharmaceutically acceptable salts of compounds of formula XI or generally salts of any of the intermediates mentioned herein, where salts are not excluded for chemical reasons the skilled person will readily understand. They can be formed where salt forming groups, such as basic or acidic groups, are present that can exist in dissociated form at least partially, e.g. in a pH range from 4 to 10 in aqueous solutions, or can be isolated especially in solid, especially crystalline, form.
- salt forming groups such as basic or acidic groups
- Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula XI or any of the intermediates mentioned herein with a basic nitrogen atom (e.g. imino or amino), especially the pharmaceutically acceptable salts.
- Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
- Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, lactic acid, fumaric acid, succinic acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, benzoic acid, methane- or ethane-sulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.
- carboxylic, phosphonic, sulfonic or sulfamic acids for example acetic acid, propionic acid,
- salts may also be formed with bases, e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethyl-amine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N′-dimethylpiperazine.
- bases e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethyl-amine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N′-dimethylpiperazine.
- a compound of formula XI or any of the intermediates mentioned herein may also form internal salts.
- any reference to “compounds”, “starting materials” and “intermediates” hereinbefore and hereinafter, especially to the compound(s) of the formula XI is to be understood as referring also to one or more salts thereof or a mixture of a corresponding free compound, intermediate or starting material and one or more salts thereof, each of which is intended to include also any solvate, metabolic precursor such as ester or amide of the compound of formula XI, or salt of any one or more of these, as appropriate and expedient and if not explicitly mentioned otherwise.
- Different crystal forms may be obtainable and then are also included.
- Starting materials are especially the compounds of the formula II, III, XII and/or XIII mentioned herein, intermediates are especially compounds of the formulae I, IV, V, VI, VII, VIII, IX, X, XIV, XVI, XVII and or XVIII, in particular I, IV, V, VI, VII, VIII, IX, X and/or XIV including the preferred definitions of these.
- the invention relates also to methods of synthesis of the intermediates of the formula formulae I, IV, V, VI, VII, VIII, IX, X, XIV, XVI, XVII and or XVIII, in particular I, IV, V, VI, VII, VIII, IX, X and/or XIV mentioned above from their respective precursors as mentioned above, including methods with the single steps of a sequence leading to a compound of the formulae I or XVIII, more than one or all steps of said synthesis and/or pharmaceutically active substances, especially renin inhibitors, most preferably aliskiren, including methods with the single steps of a sequence leading to a compound of the formula XI, more than one or all steps of said synthesis and/or pharmaceutically active substances, and/or their use in the synthesis of pharmaceutically active compounds, such as renin inhibitors, especially aliskiren.
- protecting groups may be used where appropriate or desired, even if this is not mentioned specifically, to protect functional groups that are not intended to take part in a given reaction, and they can be introduced and/or removed at appropriate or desired stages. Reactions comprising the use of protecting groups are therefore included as possible wherever reactions without specific mentioning of protection and/or deprotection are described in this specification. Within the scope of this disclosure only a readily removable group that is not a constituent of the particular desired end product is designated a “protecting group”, unless the context indicates otherwise. The protection of functional groups by such protecting groups, the protecting groups themselves, and the reactions appropriate for their introduction and removal are described for example in standard reference works, such as J. F. W.
- All the above-mentioned process steps can be carried out under reaction conditions that are known per se, preferably those mentioned specifically, in the absence or, customarily, in the presence of solvents or diluents, preferably solvents or diluents that are inert towards the reagents used and dissolve them, in the absence or presence of catalysts, condensation or neutralizing agents, for example ion exchangers, such as cation exchangers, e.g. in the H + form, depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, for example in a temperature range of from about ⁇ 100° C. to about 190° C., preferably from approximately ⁇ 80° C.
- solvents or diluents preferably solvents or diluents that are inert towards the reagents used and dissolve them
- condensation or neutralizing agents for example ion exchangers, such as cation exchangers, e.g. in the H + form, depending on
- solvents from which those solvents that are suitable for any particular reaction may be selected include those mentioned specifically or, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofurane or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, e.g.
- reaction mixtures especially in order to isolate desired compounds or intermediates, follows customary procedures and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
- the invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
- those starting materials are preferably used which result in compounds of formula I which are described as being preferred. Special preference is given to reaction conditions that are identical or analogous to those mentioned in the Examples.
- the invention relates also to novel starting compounds and intermediates described herein, especially those leading to compounds mentioned as preferred herein.
- the invention especially relates to any of the methods described hereinbefore and hereinafter that leads to aliskiren, or a pharmaceutically acceptable salt thereof.
- the enantiomer A has the shown configuration (S).
- the organocatalytic reaction was performed as in Example 1:
- reaction mixture is then added 15 ml of ethanol followed by portionwise addition of 1 g (40 mmol) of sodium borohydride.
- the reaction mixture becomes very thick and therefore 20 ml of water is added to get a clear solution. Hydrogen evolution is observed at the beginning. After 30 minutes the reduction is complete.
- the reaction mixture is quenched with aqueous 2N HCl and the pH was adjusted to 3.
- the reaction mixture is concentrated in vacuum and then extracted with 60 ml ethyl acetate. The ethyl acetate phase is washed with saturated sodium bicarbonate (4 ⁇ 20 ml) and finally with 0.5 N aqueous HCl (2 ⁇ 20 ml).
- IR (FTIR-microscopy in transmission) 3368 (CH), 2880-2966 (CH), 1552 (as-NO 2 ), 1435 (CH), 1381 (sy-NO 2 ) [cm ⁇ 1 ]
- IR (FTIR-microscopy in transmission) 2833-2972 (CH), 2729 (Fermi-Res. aldehyde., 1725(C ⁇ O), 1553 (as-NO 2 ), 1434 (CH) 1382 (sy-NO 2 )
- the enantiomeric ratio determined by HPLC at 205 nm with a Chiralpak AD-H column was 82% enantiomer A and 18% enantiomer B.
- IR (FTIR-microscopy in transmission) 3404 (br, OH), 3064, 3031 (Bn-CH), 2958, 2874 (al.CH), 1738 (C ⁇ O), 1550 (asNO 2 ) 1369 (syNO 2 ), 1175, 1092, 1074 (C—O—C), 741, 700 [cm ⁇ 1 ]
- IR (FTIR-microscopy in transmission) 3269 (br, NH 2 OH), 2957, 2872 (aliph.CH), 1687 (amide, C ⁇ O), 1455, 1367 (CH 3 ), 1094, 1074 (C—O—C), 738, 699 [cm ⁇ 1 ]
- IR (FTIR microscopy in transmission) 3239 (br, NH), 2962, 2875 (aliph. CH), 1765 (s, C ⁇ O, lacton), 1685 (s, C ⁇ O, lactam), 1180 (C ⁇ O), [cm ⁇ 1 ]
- IR (FTIR microscopy in transmission) 3396 (br, OH), 3089, 3065, 3031 (CH, Bn-H), 2959-2875 (al. CH), 1552 (as-NO 2 ), 1466, 1455 (ar.CH), 1369 (sy-NO 2 ), 1090, 1072 (C—OH, C—O—C), 739, 699 (ar, monosub.), [cm ⁇ 1 ]
- a flask is charged with 25.93 g (0.53 mol) of dry sodium cyanide and 195 ml of dry DMSO. The mixture is warmed up to an internal temperature of 90° C. To this mixture is added via a dropping funnel a solution of 100 g (0.441 mol) of ((S)-2-Chloromethyl-3-methyl-butoxymethyl)-benzene dissolved in 55 ml of dry DMSO under stirring during 1 hour. After additional 3 h at 90° C. the reaction mixture (slightly yellow suspension) is cooled to room temperature and 500 ml of water and 500 ml of toluene is added. The aqueous phase is separated and back extracted with additional 200 ml of toluene. The combined organic phases are washed twice with brine (200 ml) and are dried over Na 2 SO 4 , then filtered and evaporated in vacuum and finally in high vacuum to give almost pure nitrile as an oil.
- IR (FTIR-Microscopy in transmission) 3088, 3031 (arCH), 2960, 2873 (al.CH), 2723 (Fermi Res. Ald.), 1724 (C ⁇ O), 1465, 1368 (CH 3 ), 1103 (C—O—C), 737, 698 (monoCH), [cm ⁇ 1 ]
- the mixture is hydrogenated at normal pressure and room temperature over night. Additional Ra—Ni (0.4 g) is added in two portions with a time interval of 6 hours and hydrogenation is continued until >95% of the calculated hydrogen is consumed and HPLC showed complete conversion.
- the catalyst is filtered off and washed with 2 ⁇ 10 ml of ethanol. The solvent is removed in vacuum to give an yellow oil which was purified by chromatography to remove excess Boc 2 O giving a mixture of stereoisomers with complex proton NMR spectrum.
- the oil is crystallized from diethyl ether and hexane to give off white crystals.
- the crystals are a mixture of stereoisomers.
- the 1 H-NMR-signals of the (S,S,S,S)-stereoisomer is identified in the mixture.
- TLC shows almost complete conversion.
- 50 ml of an aqueous sodium thiosulfate solution (10%) is added. Phases are separated and the organic phase is washed with brine, dried over MgSO 4 and evaporated to give 0.73 g of a white semi-solid crystalline material which is almost pure product according to NMR and HPLC analysis.
- the crude material is recrystallised from ethyl acetate/heptane (6 ml/18 ml) to give the pure title compound BOC-lactam-lactone.
- the filtrate is washed with aqu. saturated bicarbonate solution, with water and dried over Na 2 SO 4 .
- the solvent is evaporated in vacuum to give the crude product.
- the crude product was chromatographed over silicagel with ethyl acetate/heptane (1:4) to give the product as an oil.
- the obtained aldehyde is identical by TLC, HPLC and spectroscopic data to the compound obtained in example 11.
- the BOC-protected lactam lactone of formula (I) can be further converted to aliskiren as described, e.g. in WO2007/045420.
- the following methodology can be employed:
- the reaction mixture is stirred then at ⁇ 50° C. over 3 hours.
- the reaction is cooled to a temperature of ⁇ 70° C. over night.
- aryl-lithium compound is prepared with 1.28 g aryl bromide (, (4.65 mmol) and 3 ml of n-butyllithium in the same manner as described, and added at internal temperature of ⁇ 50° C. during a time of 10 minutes to the reaction mixture. The reaction mixture is allowed to stir for 4 hours at ⁇ 50° C.
- reaction mixture is put on a mixture of 125 ml of toluene and 250 ml of a 10% citric acid solution in water at 0-5° C. during 20 minutes. The quenching is exothermic.
- the organic phase is washed with 150 ml citric acid, 10% in water, (2 ⁇ 75 ml) and 150 ml NaHCO 3 [ 8%], (2 ⁇ 75 ml).
- the organic phase is washed to a neutral pH with 150 ml of water (2 ⁇ 75 ml) and evaporated to yield crude compound as a nearly white amorphous solid.
- the reaction mixture is stirred over night at internal temperature of 50° C.
- 50 ml of water are added to the reaction solution at room temperature.
- the organic phase is washed with 50 ml of water (2 ⁇ 25 ml) and 50 ml of NaHCO 3 [ 8%], (2 ⁇ 25 ml).
- the organic phase is washed to a neutral pH with 50 ml of water (2 ⁇ 25 ml) and evaporated to yield the desired compound as a very viscous oil.
- the oil was treated and stirred at 0° C. with 10 ml of n-heptane (isomer mix) and seeded with a small amount of compound of the desired product upon the product started to crystallize.
- the flask was stored in the refrigerator over night and for another 24 hours at ⁇ 18° C.
- the product was filtered and washed with small volumes of very cold n-heptane to give after drying in vacuum the desired product, which was pure by HPLC, TLC and 1 H-NMR.
- IR (FTIR-microskop in transmission): 3358 (—NH), 1773 (lactone), 1705 (carbamate), 1518 (amide II) cm ⁇ 1 ;
- This conversion can proceed according to typical peptide coupling reactions well known in the art, e.g. in analogy to the process disclosed in EP-A-678 503 see in particular examples 124 and 131 or as disclosed in WO 02/02508, in particular example H1 on page 35 (preparation of J1).
- the removal of the group BOC is performed using standard protecting group chemistry following the procedures as described in the literature referenced below or using methods well known in the art, see e.g. EP-A-0678 503, in particular example 130, and optionally salt formation using reaction conditions as described e.g. in U.S. Pat. No. 5,559,111, see in particular example 83.
- the emulsion is stirred for additional 2 hours. Then, the reaction mixture is quenched with a 10% aqueous thiosulfate solution and stirring is continued for 30 min. The pH is then adjusted to 4 with 6N aqu. HCl. The aqueous phase is then extracted first with ethyl acetate and then with dichloromethane (8 ⁇ 50 ml) to isolate the product from the aqueous phase. The product containing CH 2 Cl 2 extracts are combined and evaporated to give an oil which is treated with diethylether (20 ml) to give white crystals which are filtered off and dried.
- the crystalline material is a mixture of the two possible stereoisomers, the syn-diastereomer and the anti-diastereomer in a ratio of 1:1.
- Mp. of the isomer mixture 130-133° C.
Abstract
Description
wherein
each R1 is independently of one another hydrogen; C1-7alkyl, C3-8cycloalkyl or benzyl, in particular both R1 are branched C3-6alkyl such as isopropyl; and
wherein Act is an activating group selected from an amino protecting group, in particular one that together with N forms a carbamate.
wherein R1 is hydrogen, C1-7alkyl, C3-8cycloalkyl or benzyl and Act is an activating group selected from an amino protecting group, in particular one that together with N forms a carbamate.
wherein R1 is hydrogen, C1-7alkyl, C3-8cycloalkyl or benzyl and Act is an activating group selected from an amino protecting group, in particular one that together with N forms a carbamate.
wherein
R1 is hydrogen, C1-7alkyl or C3-8cycloalkyl;
R2 and R3 together with N form a chiral amine moiety;
or a salt thereof said process comprising subjecting a compound of formula (II)
wherein R1 is as defined for a compound of formula (IV), or a salt thereof, to a chiral amine of formula (III)
wherein R2 and R3 are as defined for a compound of formula (IV), or a salt thereof, to form the enamine moiety. This process step as such, also forms an embodiment of the invention.
- 1.) P. W. Hickmott, Tetrahedron, 38, 1975-2050
- 2.) P. W. Hickmott, Tetrahedron, 38, 3363-3446
- 3.) Organikum, 20th ed., Wiley VCH, p. 431.
wherein
R1 is hydrogen, C1-7alkyl, such as C2-7alkyl, C3-8cycloalkyl or benzyl, in particular C1-7alkyl, such as C2-7alkyl, C3-8cycloalkyl or benzyl;
R2 and R3 together with N form a chiral amine moiety;
or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
wherein
R4 is carboxy, amido, N (mono- or di-unsubstituted or substituted C2-7alkyl) amido, unsubstituted or substituted C1-7alkyl or tetrazolyl; or a salt thereof.
wherein R9 is independently of one another C1-9alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, or phenyl, preferred is that at least one of the R9 is larger than methyl, such as tert-butyl.
wherein R1 is as defined for a compound of formula (I), or a salt thereof, said process comprising an organocatalytic nitro-Michael addition reaction of nitroethylene or a precursor thereof with a compound of formula (IV) as defined above. Preferably, this reaction takes place by directly reacting the compounds of formulae (II) and (III) as defined above with the nitroethylene or the precursor thereof without isolating the enamine of formula (IV).
wherein —O-LG is a leaving group that is eliminated under the reaction conditions to reveal the nitroethylene. Typical examples for LG are C1-7alkylcarbonyl, such as methylcarbonyl, arylcarbonyl, such as phenylcarbonyl, phthaloyl, or C1-7alkyl- or arylsulfonyl, such as methansulfonyl and toluolsulfonyl. The precursor is particularly preferably 2-nitroethyl benzoate. The precursors of formula (XII) can be prepared as known in the art, e.g. by esterification of the respective acid or acid chloride with 2-nitroethanol. Procedures are described e.g. in J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999; in particular in the relevant chapters thereof.
- 1.) A. Alexakis et al., Org. Lett. Vol. 8 (12) 2559 (2006)
- 2.) S. Ley et al., Synlett, 611 (4), 2005)
- 3.) S. Ley et al., Org. Biomol. Chem., 3, 84 (2005)
- 4.) D. Enders et al., Nature, Vol. 441, 861 (2006) and lit. cit.
- 5.) Y. Hayashi et al., Angew. Chem., Int. Ed. 44, 4212 (2005)
- 6.) C. F. Barbas et al., J.A.C.S., 128, 4966 (2006)
- 7.) C. Palomo et al., Angew. Chem., Int. Ed., 45, 5984 (2006)
- 8.) S. B. Tsogoeva et al., Eur. J. Org. Chem., 4995 (2005)
- 9.) S. B. Tsogoeva et al., Chem. Commun., 1451 (2006)
- 10.) A. Alexakis et al., Adv. Synth. Catal., 346, 1147 (2004)
- 11.) J. P. Cheng et al., Angew. Chem., Int. Ed., 45, 3093 (2006)
- 12.) N. N. Joshi et al., ARKIVOC, (2002), 167-196; review: enantiosel. Michael addition
- 13.) M. Gaunt et al., Drug Discov. Today, 12, 8-27 (2007); new organocatalysis review
- 14.) R. J. Flintoft et al., THL, 40, 4485 (1999); Addition of nitroethylene to ester Li-enolates
wherein
R1 is hydrogen, C1-7alkyl, such as C2-7alkyl, C3-8cycloalkyl or benzyl, in particular C1-7alkyl, such as C2-7alkyl, C3-8cycloalkyl or benzyl;
or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
wherein R1 is as defined for a compound of formula (I), or a salt thereof, said process comprising the reduction of the aldehyde carbonyl functionality of the compound of formula (V).
wherein
R1 is hydrogen, C1-7alkyl, such as C2-7alkyl, C3-8cycloalkyl or benzyl, in particular C1-7alkyl, such as C2-7alkyl, C3-8cycloalkyl or benzyl;
or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
wherein R1 is as defined for a compound of formula (I) and PG is a hydroxyl protecting group, or a salt thereof, said process comprising an protecting the hydroxyl functionality of the compound of formula (VI) as defined above with a protecting group.
wherein R1 is as defined for a compound of formula (I) and PG is a hydroxyl protecting group, or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
wherein R1 is as defined for a compound of formula (I) and PG is as defined for a compound of formula (VII), or a salt thereof, said process comprising a Nef reaction of the compound of formula (VII) as defined above to convert the nitro functionality to an aldehyde functionality.
- a) P. Ceccherelli, et al., Synth. Commun. 28, 3054 (1998)
- b) G. Kabalka, et al., Synth. Commun. 22, 2587 (1992)
- c) F. Urpi, et al., THL, 31, 7499 (1990)
- d) H. Chikashita et al., Synth. Commun., 17, 677 (1987)
- e) R. Ballini, M. Petrini, Tetrahedron, 60, 1017 (2004), review
wherein R1 is as defined for a compound of formula (I) and PG is a hydroxyl protecting group, or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
wherein R1 is as defined for a compound of formula (I) and PG is as defined for a compound of formula (VII), or a salt thereof, said process comprising reacting a compound of formula (XIII)
wherein R1 is as defined for a compound of formula (I) and PG is as defined for a compound of formula (VII) and X is a halogen, or a salt thereof, with a source of CN− to convert the chloride functionality to a nitrile functionality.
wherein R1 is as defined for a compound of formula (I) and PG is a hydroxyl protecting group, or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
wherein R1 is as defined for a compound of formula (I) and PG is as defined for a compound of formula (VII), or a salt thereof, said process reduction of the nitrile functionality of a compound of formula (XIV) as defined above to convert the nitrile functionality to an aldehyde functionality.
wherein both R1's are the same or different from each other and are as defined for a compound of formula (I), R5 is hydrogen or PG, and PG is as defined for a compound of formula (VII), whereby both PG's can be the same or different, or a salt thereof, said process comprising a nitro-aldol (Henry) reaction of the nitro compound of formula (VI) as defined above, when R5 is H, or the O-protected nitro compound of formula (VII) as defined above, when R5 is PG, together with the aldehyde of formula (VIII) as defined above.
- 1.) F. A. Luzzio, Tetrahedron, 57, 915-945 (2001); general review
- 2.) N. C. Barua et al., Tetrahedron: Asym. 17, 3315 (2006); general review. asym. Henry
- 3.) K. Nagasawa et al., Adv. Synth. Catal., 347, 1643 (2005); organocatalytic
- 4.) H. Hiemstra et al., Ang. Chem., Int. Ed., 45, 929 (2006); organocatalytic
- 5.) Y. Takemoto et al., Chem. Eur. J., 12, 466 (2006); organocatal. Aza-Henry
- 6.) H. Maheswara et al., Chem. Commun., 4066 (2006); Cu-II-sparteine catalyst
- 7.) K. Nagasawa et al., Eur. J. Org. Chem., 2894 (2006); organocatalytic (high syn)
- 8.) M. Shibasaki et al., Chem. Rev., 102, 2187-2209 (2002); La—Li-BINOL-catalyst
- 9.) B. Trost et al., Org. Lett., 4, 2621 (2002); Zn-Ligand catalyst
- 10.) D. Evans et al., J.A.C.S., 125, 12692 (2003); Cu-BOX-Ligand catalyst
- 11.) C. Palomo et al., Angew. Chem., 117, 3949 (2005); Zn-NME-Ligand catalyst
wherein
both R1's are the same or different from each other and are hydrogen, C1-7alkyl, such as C2-7alkyl, C3-8cycloalkyl or benzyl, in particular C1-7alkyl, such as C2-7alkyl, C3-8cycloalkyl or benzyl;
R5 is hydrogen or PG;
PG is a hydroxyl protecting group and whereby both PG's can be the same or different;
or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
wherein the definitions for R1 and PG, including the preferred ones, are as defined herein. The stereo selectivity at the hydroxyl function can be controlled by using the appropriate catalyst as described in the above literature references.
wherein both R1's are the same or different from each other and are as defined for a compound of formula (I), and Act is an activating group selected from an amino protecting group, in particular one that together with N forms a carbamate, or a salt thereof, said process comprising hydrogenation of the nitro functionality of the compound of formula (IX).
wherein
both R1's are the same or different from each other and are hydrogen, C1-7alkyl, such as C2-7alkyl, C3-8cycloalkyl or benzyl, in particular C1-7alkyl, such as C2-7alkyl, C3-8cycloalkyl or benzyl; and
wherein R1 and Act are as defined above, or a salt thereof, said process comprising selective oxidation of the primary alcohols of the compound of formula (X) as defined above to effect double ring closure into the lactone lactam.
wherein both R1's are the same or different from each other and are as defined for a compound of formula (I), R8 is C1-7alkyl, and PG is as defined for a compound of formula (VII), or a salt thereof, said process comprising a nitro-aldol (Henry) reaction of the nitro compound of formula (XV)
wherein R8 is C1-7alkyl, R1 is as defined for a compound of formula (IV) and PG is a hydroxyl protecting group, or a salt thereof, together with the aldehyde of formula (VIII) as defined above.
wherein
both R1's are the same or different from each other and are hydrogen, C1-7alkyl, C3-8cycloalkyl or benzyl, in particular hydrogen or C1-7alkyl;
R8 is C1-7alkyl;
PG is a hydroxyl protecting group;
or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
wherein the definitions for R1, R8 and PG, including the preferred ones, are as defined herein. The stereo selectivity at the hydroxyl function can be controlled by using the appropriate catalyst as described in the above literature references.
wherein both R1's are the same or different from each other and are as defined for a compound of formula (I), or a salt thereof, said process comprising hydrogenation of the nitro functionality of the compound of formula (XVI) and ring closure to form the lactam, said process, comprising as a concomitant or separate step the removal of the protecting group PG to reveal the hydroxyl functionality.
wherein
both R1's are the same or different from each other and are hydrogen, C1-7alkyl, such as C2-7alkyl, C3-8cycloalkyl or benzyl;
or a salt thereof, is a valuable intermediate of the process of preparing renin inhibitors such as aliskiren, in an efficient manner. Therefore such compounds also form an embodiment of the invention.
wherein R1 are as defined above, or a salt thereof, said process comprising selective oxidation of the primary alcohol of the compound of formula (XVII) as defined above to effect ring closure into the lactone lactam.
wherein Act is an activating group selected from an amino protecting group, in particular one that together with N forms a carbamate.
wherein R1 is hydrogen, C1-7alkyl, C3-8cycloalkyl or benzyl and Act is an activating group selected from an amino protecting group, in particular one that together with N forms a carbamate.
wherein R1 is hydrogen, C1-7alkyl, C3-8cycloalkyl or benzyl and Act is an activating group selected from an amino protecting group, in particular one that together with N forms a carbamate.
wherein R1 is as defined for a compound of formula (I), R6 is halogen, hydroxyl, C1-6halogenalkyl, C1-6alkoxy-C1-6alkyloxy or C1-6alkoxy-C1-6alkyl; R7 is halogen, hydroxyl, C1-4alkyl or C1-4alkoxy, or a salt thereof, comprising one or more of the following steps either individually or in any combination:
-
- the manufacture of a compound of the formula IV as defined above,
- the manufacture of a compound of the formula V as defined above,
- the manufacture of a compound of the formula VI as defined above,
- the manufacture of a compound of the formula VII as defined above,
- the manufacture of a compound of the formula VIII as defined above,
- the manufacture of a compound of the formula IX as defined above,
- the manufacture of a compound of the formula X as defined above, and
- the manufacture of a compound of the formula as defined above.
Abbreviations: |
δ | chemical shift |
μl | microliter |
Ac | acetyl |
Bn | benzyl |
Boc | tert-butoxycarbonyl |
BOC2O | di-tert-butyl carbonate |
Cbz | benzyl carbamate |
Cbz-Cl | benzyl chloroformate |
DCM | dichloromethane |
de | diastereomeric excess |
DIBAH | diisobutylaluminium hydride |
DMAP | 4-(dimethylamino)pyridine |
DMF | N,N-dimethylformamide |
DMPU | 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone |
DMSO | dimethylsulfoxide |
ee | enantiomeric excess |
ES | electrospray |
ESI | electrospray ionisation |
Et | ethyl |
EtOAc | ethyl acetate |
FTIR | fourier transform infrared spectroscopy |
h | hour(s) |
HNMR | proton nuclear magnetic resonance |
HOBt | 1-hydroxybenzotriazole |
HPLC | high performance liquid chromatography |
i-Pr | isopropyl |
iPrOAc | isopropyl acetate |
IR | infrared |
KHMDS | potassium bis(trimethylsilyl)amide |
L | liter |
LCMS | liquid chromatography-mass spectrometry |
LDA | lithium diisopropylamide |
LHMDS | lithium bis(trimethylsilyl)amide |
LRMS | low resolution mass spectroscopy |
M | molarity |
m/e | mass-to-charge ratio |
Me | methyl |
mg | milligram |
min | minute(s) |
mL | milliliter |
mmol(s) | millimole(s) |
mol(s) | mole(s) |
MS | mass spectrometry |
NaHMDS | sodium bis(trimethylsilyl)amide |
nm | nanometer |
NMR | nuclear magnetic resonance |
Pd/C | palladium on carbon |
Ph | phenyl |
Piv | pivaloyl |
Piv-Cl | pivaloyl chloride |
ppm | parts per million |
psi | pounds per square inch |
RT | room temperature |
SEM | 2-(Trimethylsilyl)ethoxymethyl |
SEM-Cl | (2-chloromethoxyethyl)-trimethylsilane |
TBDMS | tertbutyldimethylsilyl |
TBME | tertbutylmethylether |
TEMPO | 2,2,6,6-tetramethyl-1-piperidinyloxy |
TES | triethylsilyl |
TFA | trifluoroacetic acid |
THF | tetrahydrofuran |
TLC | thin layer chromatography |
TMEDA | N,N,N,N-tetramethylethylenediamine |
TMS | trimethylsilyl |
TPAP | tetrapropylammonium perruthenate |
tR | retention time |
Ts | tosylate/tosyl |
-
- (starting material see: J. Maibaum et al., Helv. Ch. Acta, 86, 2848, 2003)
- a) P. Ceccherelli, et al., Synth. Commun., 28, 3054 (1998)
- b) G. Kabalka, et al., Synth. Commun., 22, 2587 (1992)
- c) F. Urpi, et al., THL, 31, 7499 (1990)
- d) H. Chikashita et al., Synth. Commun., 17, 677 (1987)
- e) R. Ballini, M. Petrini, Tetrahedron, 60, 1017 (2004), review
Claims (39)
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US10138252B1 (en) * | 2017-04-24 | 2018-11-27 | Purdue Research Foundation | Lactones |
Families Citing this family (10)
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RU2473565C2 (en) | 2006-04-07 | 2013-01-27 | Аерпио Терапетикс, Инк. | HUMAN PROTEIN TYROSINE PHOSPHATASE BETA BINDING ANTIBODIES (HPTPβ), AND USE THEREOF |
SI2189442T1 (en) * | 2008-11-20 | 2015-03-31 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process and intermediates for the preparation of aliskiren |
MX347956B (en) * | 2009-08-11 | 2017-05-16 | Massachusetts Inst Technology | The ring opening of lactones and lactams. |
WO2011048523A1 (en) * | 2009-10-21 | 2011-04-28 | CarboDesign LLC | Process for the manufacture of enantiomerically pure aryloctanoic acids as aliskiren |
WO2011051853A1 (en) * | 2009-10-29 | 2011-05-05 | CarboDesign LLC | Manufacturing process for preparing enaniomerically pure 8- aryloctanoic acid derivatives such as aliskiren |
WO2011064790A1 (en) * | 2009-11-30 | 2011-06-03 | Avra Laboratories Pvt. Ltd | A novel process for making aliskiren, its novel intermediates and certain novel compounds |
EP2523934A1 (en) * | 2010-02-10 | 2012-11-21 | Ratiopharm GmbH | Salts of aliskiren |
CN102241650B (en) * | 2010-05-14 | 2014-05-07 | 浙江九洲药业股份有限公司 | Intermediate compound for preparing aliskiren and related preparation method |
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US8703976B2 (en) | 2011-10-02 | 2014-04-22 | Milan Soukup | Manufacturing process for 8-aryloctanoic acids such as Aliskiren |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4219660A (en) * | 1977-06-24 | 1980-08-26 | Hoffmann-La Roche Inc. | Conjugated diene derivatives |
EP0678503A1 (en) | 1994-04-18 | 1995-10-25 | Ciba-Geigy Ag | Delta-amino-gamma-hydroxy-omega-aryl alkanoic acid amides with enzyme especially renin inhibiting activities |
US5606078A (en) | 1994-04-18 | 1997-02-25 | Ciba-Geigy Corporation | 3,5-Disubstituted tetrahydrofuran-2-ones |
US5659065A (en) | 1994-04-18 | 1997-08-19 | Novartis Corporation | Alpha-aminoalkanoic acids and reduction products |
WO2007045420A2 (en) | 2005-10-17 | 2007-04-26 | Novartis Ag | 3-alkyl-5- (4-alkyl-5-oxo-tetrahydrofutran-2-yl) pyrrolidin-2-one derivatives as intermediates in the synthesis of renin inhibitors |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL153123A0 (en) * | 2000-06-30 | 2003-06-24 | Bristol Myers Squibb Co | N-ureidoheterocycloalkyl-piperidine derivatives and pharmaceutical compositions containing the same |
EP1758899A1 (en) * | 2004-06-03 | 2007-03-07 | Brandeis University | Asymmetric michael and aldol addition using bifunctional cinchona-alkaloid-based catalysts |
JP4639327B2 (en) * | 2004-07-16 | 2011-02-23 | 国立大学法人高知大学 | Optically active aminopyridyl group-containing pyrrolidine derivative and asymmetric synthesis method using the same |
WO2007013681A1 (en) * | 2005-07-29 | 2007-02-01 | Nagase & Co., Ltd. | Guanidine-thiourea compound and process for production of nitro alcohol using the same |
-
2008
- 2008-04-01 JP JP2010501501A patent/JP2010523523A/en active Pending
- 2008-04-01 EP EP08735661A patent/EP2142497A1/en not_active Withdrawn
- 2008-04-01 AU AU2008234834A patent/AU2008234834B2/en not_active Ceased
- 2008-04-01 CN CN200880015223A patent/CN101679213A/en active Pending
- 2008-04-01 WO PCT/EP2008/053891 patent/WO2008119804A1/en active Application Filing
- 2008-04-01 NZ NZ579792A patent/NZ579792A/en not_active IP Right Cessation
- 2008-04-01 BR BRPI0809678-3A2A patent/BRPI0809678A2/en not_active IP Right Cessation
- 2008-04-01 US US12/594,414 patent/US8338620B2/en not_active Expired - Fee Related
- 2008-04-01 KR KR1020097022892A patent/KR20100016137A/en not_active Application Discontinuation
- 2008-04-01 CA CA002681203A patent/CA2681203A1/en not_active Abandoned
- 2008-04-01 RU RU2009140306/04A patent/RU2009140306A/en not_active Application Discontinuation
- 2008-04-01 MX MX2009010699A patent/MX2009010699A/en not_active Application Discontinuation
-
2009
- 2009-09-17 ZA ZA200906490A patent/ZA200906490B/en unknown
- 2009-09-21 IL IL201054A patent/IL201054A0/en unknown
- 2009-10-01 GT GT200900259A patent/GT200900259A/en unknown
- 2009-10-01 CO CO09107976A patent/CO6231027A2/en not_active Application Discontinuation
- 2009-10-02 TN TNP2009000401A patent/TN2009000401A1/en unknown
- 2009-10-21 MA MA32298A patent/MA31325B1/en unknown
- 2009-10-30 EC EC2009009708A patent/ECSP099708A/en unknown
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4219660A (en) * | 1977-06-24 | 1980-08-26 | Hoffmann-La Roche Inc. | Conjugated diene derivatives |
EP0678503A1 (en) | 1994-04-18 | 1995-10-25 | Ciba-Geigy Ag | Delta-amino-gamma-hydroxy-omega-aryl alkanoic acid amides with enzyme especially renin inhibiting activities |
US5559111A (en) | 1994-04-18 | 1996-09-24 | Ciba-Geigy Corporation | δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides |
US5606078A (en) | 1994-04-18 | 1997-02-25 | Ciba-Geigy Corporation | 3,5-Disubstituted tetrahydrofuran-2-ones |
US5627182A (en) | 1994-04-18 | 1997-05-06 | Ciba Geigy Corporation | δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides |
US5646143A (en) | 1994-04-18 | 1997-07-08 | Ciba-Geigy Corporation | δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides |
US5654445A (en) | 1994-04-18 | 1997-08-05 | Ciba-Geigy Corporation | δ-amino-γ-hydroxy-ω-aryl-alkanoic acids |
US5659065A (en) | 1994-04-18 | 1997-08-19 | Novartis Corporation | Alpha-aminoalkanoic acids and reduction products |
US5705658A (en) | 1994-04-18 | 1998-01-06 | Novartis Corporation | Azido containing tetrahydro furan compounds |
WO2007045420A2 (en) | 2005-10-17 | 2007-04-26 | Novartis Ag | 3-alkyl-5- (4-alkyl-5-oxo-tetrahydrofutran-2-yl) pyrrolidin-2-one derivatives as intermediates in the synthesis of renin inhibitors |
US7772405B2 (en) * | 2005-10-17 | 2010-08-10 | Novartis Ag | 3-alkyl-5- (4-alkyl-5-oxo-tetrahydrofutran-2-yl) pyrrolidin-2-one derivatives as intermediates in the synthesis of renin inhibitors |
Non-Patent Citations (18)
Title |
---|
(1952).Zhi,et al., Synthesis of substituted 6-anilinouracils and their inhibition of DNA polymerase IIIC and gram-positive bacterial growth, J. Med. Chem., 46, 2731-2739 (2003). |
Andrey et al., the use of n-alkyl-2,2′-bipyrrolidine derivatives as organocatalysts for the asymmetric michael addition of ketones and aldehydes to nitroolefins, Advanced Sythesis & Catalysis, 346(9+10), pp. 1147-1168 (2004). |
Andrey et al., the use of n-alkyl-2,2'-bipyrrolidine derivatives as organocatalysts for the asymmetric michael addition of ketones and aldehydes to nitroolefins, Advanced Sythesis & Catalysis, 346(9+10), pp. 1147-1168 (2004). |
Barluenga et al., "Communications to the Editor", J. Am. Chem. Soc., 121, pp. 4516-4517 (1999). |
Bergel'son et al. Izvestiya Akademii Nauk SSR, Seriya Khimicheskaya 1964, 8, (Abstract provided). * |
Bergel'son et al. Izvestiya Akademii Nauk SSR, Seriya Khimicheskaya 1964, 8, 1453-56. * |
Haug et al., Synthesis of a gin-phe hydroxy-ethylene dipeptide isostere, Organic Letters, vol. 6, No. 25, pp. 4783-4786 (2004). |
Hayashi et al., "Diphenylprolinol silyl ethers as efficient organocatalysts for the asymmetric michael reaction of aldehydes and nitroalkenes", Angew. Chem. Int. 44, pp. 4212-4215 (2005). |
Hurd et al., "Ring-chin tautomerism of hydroxy aldehydes", Journal of the American Chemical society, vol. 74, pp. 5324-5329 (1952). |
Ito et al, "Trimethylchlorosilane induced ring opening of 2-alkyloxazolidines to enamine derivatives" vol. 26, No. 43, pp. 5303-5306 (195). |
Kim et al. Synlett 2000, 8, 1151-1153. * |
Melchiorre et al., "Direct enantioselective michael addition of aldehydes to vinyl ketones catalyzed by chiral amines", JOC Article (2003). |
Mitchell et al. A homo-proline tetrazole as an improved organocatalyst for the asymmetric michael addition of carbonyl compounds to nitro-olefins, SYNLETT 4, pp. 611-614 (2004). |
Paquette et al. J. Org. Chem. 2003, 68(16), 6097-6107. * |
Registry, ACS, STN on the Web, pp. 1-4, Nov. 16, 1984. |
Schlinck, Julius, "Pyrrolidine", J. Chem. Soc., Abstr. 76, I, pp. 539-541, Jan. 1, 1899, downloaded Jun. 5, 2012, http://pubs.rsc.org. |
Schlinck, Julius, "Pyrrolidine", J. Chem. Soc., Berichte der Deutschen Chemischen Gesellschaft 32, pp. 947-958 (1899). |
Shechter et al., "Addition reactions of nitroalkanes with acrolein and methyl vinyl ketone. Selective reduction of nitrocarbonyl compounds to nitrocarbinols", Journal of the American Chemical Society 74, pp. 3664-3668 (1952). |
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US10138252B1 (en) * | 2017-04-24 | 2018-11-27 | Purdue Research Foundation | Lactones |
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